Peitao Wu1, Jee-Young Moon2, Iyas Daghlas3,4, Giulianini Franco5, Bianca C Porneala6, Fariba Ahmadizar7, Tom G Richardson8,9, Jonas L Isaksen10, Georgy Hindy11, Jie Yao12, Colleen M Sitlani13, Laura M Raffield14, Lisa R Yanek15, Mary F Feitosa16, Rafael R C Cuadrat17,18, Qibin Qi2, M Arfan Ikram7, Christina Ellervik19,20, Ulrika Ericson11, Mark O Goodarzi21, Jennifer A Brody13, Leslie Lange22, Josep M Mercader4,23,24, Dhananjay Vaidya15, Ping An16, Matthias B Schulze17,18,25, Lluis Masana26,27, Mohsen Ghanbari7, Morten S Olesen28,29, Jianwen Cai30, Xiuqing Guo12, James S Floyd13,31, Susanne Jäger17,18, Michael A Province16, Rita R Kalyani15, Bruce M Psaty13,31,32, Marju Orho-Melander11, Paul M Ridker5,24, Jørgen K Kanters10, Andre Uitterlinden7,33, George Davey Smith8, Dipender Gill9,34,35,36, Robert C Kaplan2,37, Maryam Kavousi7, Sridharan Raghavan38,39, Daniel I Chasman3,4, Jerome I Rotter12, James B Meigs4,6,24, Jose C Florez4,23,24, Josée Dupuis1, Ching-Ti Liu1, Jordi Merino4,23,24,26. 1. 1Department of Biostatistics, Boston University School of Public Health, Boston, MA. 2. 2Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY. 3. 3Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA. 4. 4Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA. 5. 5Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA. 6. 6Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA. 7. 7Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands. 8. 8MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, U.K. 9. 9Novo Nordisk Research Centre Oxford, Old Road Campus, Oxford, U.K. 10. 10Laboratory of Experimental Cardiology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark. 11. 11Department of Clinical Sciences, Skåne University Hospital Malmo Clinical Research Center, Lund University, Malmo, Sweden. 12. 12Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA. 13. 13Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA. 14. 14Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC. 15. 15Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD. 16. 16Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO. 17. 17Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany. 18. 18German Center for Diabetes Research, Neuherberg, Germany. 19. 19Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. 20. 20Department of Research, Region Zealand, Sorø, Denmark. 21. 21Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA. 22. 22Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO. 23. 23Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA. 24. 24Department of Medicine, Harvard Medical School, Boston, MA. 25. 25Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany. 26. 26Vascular Medicine and Metabolism Unit, Research Unit on Lipids and Atherosclerosis, Sant Joan University Hospital, Rovira i Virgil University, IISPV, Reus, Spain. 27. 27Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain. 28. 28Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark. 29. 29Laboratory for Molecular Cardiology, Department of Cardiology, The Heart Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. 30. 30Collaborative Studies Coordinating Center, Department of Biostatistics, The University of North Carolina at Chapel Hill, NC. 31. 31Department of Epidemiology, University of Washington, Seattle, WA. 32. 32Department of Health Services, University of Washington, Seattle, WA. 33. 33Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands. 34. 34Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, U.K. 35. 35Clinical Pharmacology and Therapeutics Section, Institute of Medical and Biomedical Education and Institute for Infection and Immunity, St George's, University of London, London, U.K. 36. 36Clinical Pharmacology Group, Pharmacy and Medicines Directorate, St George's University Hospitals NHS Foundation Trust, London, U.K. 37. 37Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle WA. 38. 38Department of Veterans Affairs Medical Center, Eastern Colorado Health Care System, Denver, CO. 39. 39Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado School of Medicine, Denver, CO.
Abstract
OBJECTIVE: LDL cholesterol (LDLc)-lowering drugs modestly increase body weight and type 2 diabetes risk, but the extent to which the diabetogenic effect of lowering LDLc is mediated through increased BMI is unknown. RESEARCH DESIGN AND METHODS: We conducted summary-level univariable and multivariable Mendelian randomization (MR) analyses in 921,908 participants to investigate the effect of lowering LDLc on type 2 diabetes risk and the proportion of this effect mediated through BMI. We used data from 92,532 participants from 14 observational studies to replicate findings in individual-level MR analyses. RESULTS: A 1-SD decrease in genetically predicted LDLc was associated with increased type 2 diabetes odds (odds ratio [OR] 1.12 [95% CI 1.01, 1.24]) and BMI (β = 0.07 SD units [95% CI 0.02, 0.12]) in univariable MR analyses. The multivariable MR analysis showed evidence of an indirect effect of lowering LDLc on type 2 diabetes through BMI (OR 1.04 [95% CI 1.01, 1.08]) with a proportion mediated of 38% of the total effect (P = 0.03). Total and indirect effect estimates were similar across a number of sensitivity analyses. Individual-level MR analyses confirmed the indirect effect of lowering LDLc on type 2 diabetes through BMI with an estimated proportion mediated of 8% (P = 0.04). CONCLUSIONS: These findings suggest that the diabetogenic effect attributed to lowering LDLc is partially mediated through increased BMI. Our results could help advance understanding of adipose tissue and lipids in type 2 diabetes pathophysiology and inform strategies to reduce diabetes risk among individuals taking LDLc-lowering medications.
OBJECTIVE: LDL cholesterol (LDLc)-lowering drugs modestly increase body weight and type 2 diabetes risk, but the extent to which the diabetogenic effect of lowering LDLc is mediated through increased BMI is unknown. RESEARCH DESIGN AND METHODS: We conducted summary-level univariable and multivariable Mendelian randomization (MR) analyses in 921,908 participants to investigate the effect of lowering LDLc on type 2 diabetes risk and the proportion of this effect mediated through BMI. We used data from 92,532 participants from 14 observational studies to replicate findings in individual-level MR analyses. RESULTS: A 1-SD decrease in genetically predicted LDLc was associated with increased type 2 diabetes odds (odds ratio [OR] 1.12 [95% CI 1.01, 1.24]) and BMI (β = 0.07 SD units [95% CI 0.02, 0.12]) in univariable MR analyses. The multivariable MR analysis showed evidence of an indirect effect of lowering LDLc on type 2 diabetes through BMI (OR 1.04 [95% CI 1.01, 1.08]) with a proportion mediated of 38% of the total effect (P = 0.03). Total and indirect effect estimates were similar across a number of sensitivity analyses. Individual-level MR analyses confirmed the indirect effect of lowering LDLc on type 2 diabetes through BMI with an estimated proportion mediated of 8% (P = 0.04). CONCLUSIONS: These findings suggest that the diabetogenic effect attributed to lowering LDLc is partially mediated through increased BMI. Our results could help advance understanding of adipose tissue and lipids in type 2 diabetes pathophysiology and inform strategies to reduce diabetes risk among individuals taking LDLc-lowering medications.
Authors: Tayeba Khan; Mark P Hamilton; Dorothy I Mundy; Streamson C Chua; Philipp E Scherer Journal: Endocrinology Date: 2009-10-09 Impact factor: 4.736
Authors: David Preiss; Sreenivasa Rao Kondapally Seshasai; Paul Welsh; Sabina A Murphy; Jennifer E Ho; David D Waters; David A DeMicco; Philip Barter; Christopher P Cannon; Marc S Sabatine; Eugene Braunwald; John J P Kastelein; James A de Lemos; Michael A Blazing; Terje R Pedersen; Matti J Tikkanen; Naveed Sattar; Kausik K Ray Journal: JAMA Date: 2011-06-22 Impact factor: 56.272
Authors: Daniel I Swerdlow; David Preiss; Karoline B Kuchenbaecker; Michael V Holmes; Jorgen E L Engmann; Tina Shah; Reecha Sofat; Stefan Stender; Paul C D Johnson; Robert A Scott; Maarten Leusink; Niek Verweij; Stephen J Sharp; Yiran Guo; Claudia Giambartolomei; Christina Chung; Anne Peasey; Antoinette Amuzu; KaWah Li; Jutta Palmen; Philip Howard; Jackie A Cooper; Fotios Drenos; Yun R Li; Gordon Lowe; John Gallacher; Marlene C W Stewart; Ioanna Tzoulaki; Sarah G Buxbaum; Daphne L van der A; Nita G Forouhi; N Charlotte Onland-Moret; Yvonne T van der Schouw; Renate B Schnabel; Jaroslav A Hubacek; Ruzena Kubinova; Migle Baceviciene; Abdonas Tamosiunas; Andrzej Pajak; Roman Topor-Madry; Urszula Stepaniak; Sofia Malyutina; Damiano Baldassarre; Bengt Sennblad; Elena Tremoli; Ulf de Faire; Fabrizio Veglia; Ian Ford; J Wouter Jukema; Rudi G J Westendorp; Gert Jan de Borst; Pim A de Jong; Ale Algra; Wilko Spiering; Anke H Maitland-van der Zee; Olaf H Klungel; Anthonius de Boer; Pieter A Doevendans; Charles B Eaton; Jennifer G Robinson; David Duggan; John Kjekshus; John R Downs; Antonio M Gotto; Anthony C Keech; Roberto Marchioli; Gianni Tognoni; Peter S Sever; Neil R Poulter; David D Waters; Terje R Pedersen; Pierre Amarenco; Haruo Nakamura; John J V McMurray; James D Lewsey; Daniel I Chasman; Paul M Ridker; Aldo P Maggioni; Luigi Tavazzi; Kausik K Ray; Sreenivasa Rao Kondapally Seshasai; JoAnn E Manson; Jackie F Price; Peter H Whincup; Richard W Morris; Debbie A Lawlor; George Davey Smith; Yoav Ben-Shlomo; Pamela J Schreiner; Myriam Fornage; David S Siscovick; Mary Cushman; Meena Kumari; Nick J Wareham; W M Monique Verschuren; Susan Redline; Sanjay R Patel; John C Whittaker; Anders Hamsten; Joseph A Delaney; Caroline Dale; Tom R Gaunt; Andrew Wong; Diana Kuh; Rebecca Hardy; Sekar Kathiresan; Berta A Castillo; Pim van der Harst; Eric J Brunner; Anne Tybjaerg-Hansen; Michael G Marmot; Ronald M Krauss; Michael Tsai; Josef Coresh; Ronald C Hoogeveen; Bruce M Psaty; Leslie A Lange; Hakon Hakonarson; Frank Dudbridge; Steve E Humphries; Philippa J Talmud; Mika Kivimäki; Nicholas J Timpson; Claudia Langenberg; Folkert W Asselbergs; Mikhail Voevoda; Martin Bobak; Hynek Pikhart; James G Wilson; Alex P Reiner; Brendan J Keating; Aroon D Hingorani; Naveed Sattar Journal: Lancet Date: 2014-09-24 Impact factor: 79.321
Authors: Robert A Scott; Nicholas J Wareham; Luca A Lotta; Stephen J Sharp; Stephen Burgess; John R B Perry; Isobel D Stewart; Sara M Willems; Jian'an Luan; Eva Ardanaz; Larraitz Arriola; Beverley Balkau; Heiner Boeing; Panos Deloukas; Nita G Forouhi; Paul W Franks; Sara Grioni; Rudolf Kaaks; Timothy J Key; Carmen Navarro; Peter M Nilsson; Kim Overvad; Domenico Palli; Salvatore Panico; Jose-Ramón Quirós; Elio Riboli; Olov Rolandsson; Carlotta Sacerdote; Elena C Salamanca; Nadia Slimani; Annemieke Mw Spijkerman; Anne Tjonneland; Rosario Tumino; Daphne L van der A; Yvonne T van der Schouw; Mark I McCarthy; Inês Barroso; Stephen O'Rahilly; David B Savage; Naveed Sattar; Claudia Langenberg Journal: JAMA Date: 2016-10-04 Impact factor: 56.272
Authors: Gibran Hemani; Jie Zheng; Benjamin Elsworth; Tom R Gaunt; Philip C Haycock; Kaitlin H Wade; Valeriia Haberland; Denis Baird; Charles Laurin; Stephen Burgess; Jack Bowden; Ryan Langdon; Vanessa Y Tan; James Yarmolinsky; Hashem A Shihab; Nicholas J Timpson; David M Evans; Caroline Relton; Richard M Martin; George Davey Smith Journal: Elife Date: 2018-05-30 Impact factor: 8.140
Authors: Alice R Carter; Dipender Gill; Neil M Davies; Amy E Taylor; Taavi Tillmann; Julien Vaucher; Robyn E Wootton; Marcus R Munafò; Gibran Hemani; Rainer Malik; Sudha Seshadri; Daniel Woo; Stephen Burgess; George Davey Smith; Michael V Holmes; Ioanna Tzoulaki; Laura D Howe; Abbas Dehghan Journal: BMJ Date: 2019-05-22
Authors: Brian A Ference; Jennifer G Robinson; Robert D Brook; Alberico L Catapano; M John Chapman; David R Neff; Szilard Voros; Robert P Giugliano; George Davey Smith; Sergio Fazio; Marc S Sabatine Journal: N Engl J Med Date: 2016-12-01 Impact factor: 91.245
Authors: Robert A Scott; Laura J Scott; Reedik Mägi; Letizia Marullo; Kyle J Gaulton; Marika Kaakinen; Natalia Pervjakova; Tune H Pers; Andrew D Johnson; John D Eicher; Anne U Jackson; Teresa Ferreira; Yeji Lee; Clement Ma; Valgerdur Steinthorsdottir; Gudmar Thorleifsson; Lu Qi; Natalie R Van Zuydam; Anubha Mahajan; Han Chen; Peter Almgren; Ben F Voight; Harald Grallert; Martina Müller-Nurasyid; Janina S Ried; Nigel W Rayner; Neil Robertson; Lennart C Karssen; Elisabeth M van Leeuwen; Sara M Willems; Christian Fuchsberger; Phoenix Kwan; Tanya M Teslovich; Pritam Chanda; Man Li; Yingchang Lu; Christian Dina; Dorothee Thuillier; Loic Yengo; Longda Jiang; Thomas Sparso; Hans A Kestler; Himanshu Chheda; Lewin Eisele; Stefan Gustafsson; Mattias Frånberg; Rona J Strawbridge; Rafn Benediktsson; Astradur B Hreidarsson; Augustine Kong; Gunnar Sigurðsson; Nicola D Kerrison; Jian'an Luan; Liming Liang; Thomas Meitinger; Michael Roden; Barbara Thorand; Tõnu Esko; Evelin Mihailov; Caroline Fox; Ching-Ti Liu; Denis Rybin; Bo Isomaa; Valeriya Lyssenko; Tiinamaija Tuomi; David J Couper; James S Pankow; Niels Grarup; Christian T Have; Marit E Jørgensen; Torben Jørgensen; Allan Linneberg; Marilyn C Cornelis; Rob M van Dam; David J Hunter; Peter Kraft; Qi Sun; Sarah Edkins; Katharine R Owen; John R B Perry; Andrew R Wood; Eleftheria Zeggini; Juan Tajes-Fernandes; Goncalo R Abecasis; Lori L Bonnycastle; Peter S Chines; Heather M Stringham; Heikki A Koistinen; Leena Kinnunen; Bengt Sennblad; Thomas W Mühleisen; Markus M Nöthen; Sonali Pechlivanis; Damiano Baldassarre; Karl Gertow; Steve E Humphries; Elena Tremoli; Norman Klopp; Julia Meyer; Gerald Steinbach; Roman Wennauer; Johan G Eriksson; Satu Mӓnnistö; Leena Peltonen; Emmi Tikkanen; Guillaume Charpentier; Elodie Eury; Stéphane Lobbens; Bruna Gigante; Karin Leander; Olga McLeod; Erwin P Bottinger; Omri Gottesman; Douglas Ruderfer; Matthias Blüher; Peter Kovacs; Anke Tonjes; Nisa M Maruthur; Chiara Scapoli; Raimund Erbel; Karl-Heinz Jöckel; Susanne Moebus; Ulf de Faire; Anders Hamsten; Michael Stumvoll; Panagiotis Deloukas; Peter J Donnelly; Timothy M Frayling; Andrew T Hattersley; Samuli Ripatti; Veikko Salomaa; Nancy L Pedersen; Bernhard O Boehm; Richard N Bergman; Francis S Collins; Karen L Mohlke; Jaakko Tuomilehto; Torben Hansen; Oluf Pedersen; Inês Barroso; Lars Lannfelt; Erik Ingelsson; Lars Lind; Cecilia M Lindgren; Stephane Cauchi; Philippe Froguel; Ruth J F Loos; Beverley Balkau; Heiner Boeing; Paul W Franks; Aurelio Barricarte Gurrea; Domenico Palli; Yvonne T van der Schouw; David Altshuler; Leif C Groop; Claudia Langenberg; Nicholas J Wareham; Eric Sijbrands; Cornelia M van Duijn; Jose C Florez; James B Meigs; Eric Boerwinkle; Christian Gieger; Konstantin Strauch; Andres Metspalu; Andrew D Morris; Colin N A Palmer; Frank B Hu; Unnur Thorsteinsdottir; Kari Stefansson; Josée Dupuis; Andrew P Morris; Michael Boehnke; Mark I McCarthy; Inga Prokopenko Journal: Diabetes Date: 2017-05-31 Impact factor: 9.337